Derivatives of 1-piperazine- and 1-homopiperazine-carboxylates, preparation method thereof and use of same as inhibitors of the faah enzyme

ABSTRACT

The invention relates to a compound having general formula (I): 
     
       
         
         
             
             
         
       
     
     Wherein m, R 1  and R 2  are as defined herein. The invention also relates to the use of the compound in therapeutics. More specifically, the compounds of the invention are inhibitors of the FAAH enzyme, and therefore, can be used for the treatment of various disorders associated with FAAH enzyme, which include in a non-limiting manner, pain, eating disorders, neurological and psychiatric pathologies, among other disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/473,284, filed Jun. 22, 2006, now allowed, which is a continuation ofInternational application No. PCT/FR2004/003,289, filed Dec. 17, 2004,both of which are incorporated herein by reference in their entirety;which claims the benefit of priority of French Patent Application No.03/15,248, filed Dec. 23, 2003

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to 1-piperazine- and 1-homopiperazine-carboxylatederivatives, and to the preparation and therapeutic application thereof.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula (I)

in which

m represents an integer equal to 1 or 2;

R₁ represents a group chosen especially from a phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, triazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl,tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl,quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzofuryl,dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzimidazolyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl,imidazopyrimidinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl,thiazolopyridyl or isothiazolopyridyl,

this group being optionally substituted with one or more groups R₃,which may be identical or different, or with a group R₄;

R₂ represents a group of general formula CHR₅CONHR₆,

R₃ represents a halogen atom or a hydroxyl, cyano, nitro, C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-thioalkyl, C₁₋₆-fluoroalkyl, C₁₋₆-fluoroalkoxy,—O—(C₂₋₃-alkylene)-, —O—(C₁₋₃-alkylene)-O—, C₁₋₆-fluorothioalkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkylene, piperidyl, benzyloxy,piperazinyl, pyrrolidinyl, morpholinyl, phenyloxy, NR₇R₈, NHCOR₇,NHSO₂R₇, COR₇, CO₂R₇, CONR₇R₈, SO₂R₇ or SO₂NR₇R₈ group,

R₄ represents a group chosen especially from a phenyl, benzofuryl,naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl,imidazolpyrimidinyl, benzothienyl, indolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl,indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl,thienopyridyl, dihydrothienopyridyl, imidazopyridyl, imidazopyrimidinyl,pyrazopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl orisothiazolopyridyl;

the group(s) R₄ possibly being substituted with one or more groups R₃,which may be identical or different,

R₅ represents a hydrogen atom or a C₁₋₃-alkyl group;

R₆ represents a hydrogen atom or a C₁₋₆-alkyl, C₃₋₇-cycloalkyl orC₃₋₇-cycloalkyl-C₁₋₃-alkylene group;

R₇ and R₈ represent, independently of each other, a hydrogen atom, aC₁₋₃-alkyl group or a phenyl group.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of general formula (I), a first sub-group ofcompounds consists of compounds for which:

m represents an integer equal to 1 or 2; and/or

R₁ represents a group chosen especially from a phenyl, pyridyl,pyrimidinyl, pyrazinyl, naphthyl, quinolyl, isoquinolyl, benzisoxazolyl,thienopyridyl, this group being optionally substituted with one or moregroups R₃, more particularly with one or two groups R₃, which may beidentical or different; and/or

R₂ represents a group of general formula CHR₅CONHR_(6;) and/or

R₃ represents a halogen atom, more particularly a chlorine, a bromine ora fluorine, or a cyano group, C₁₋₆-alkyl, more particularly a methyl,ethyl, n-propyl or isobutyl, C₁₋₆-alkoxy, more particularly a methoxy,C₁₋₆-fluoroalkyl, more particularly a CF₃, C₁₋₆-fluoroalkoxy, moreparticularly an —OCH₂CF₃, —O—(C₂₋₃-alkylene)-, more particularly an—O—(CH₂)₃—, phenyloxy; and/or

R₅ represents a hydrogen atom; and/or

R₆ represents a hydrogen atom or a C₁₋₆-alkyl group, more particularly amethyl.

Among the compounds of general formula (I), a second sub-group ofcompounds consists of compounds for which:

m is equal to 1; and/or

R₁ represents a group chosen especially from a pyridyl, pyrimidinyl,pyrazinyl, quinolyl and isoquinolyl, this group being optionallysubstituted with a group R₃; and/or

R₂ represents a group of general formula CHR₅CONHR_(6;) and/or

R₃ represents a halogen atom, more particularly a chlorine, or aC₁₋₆-alkyl group, more particularly a methyl, ethyl, n-propyl orisobutyl, C₁₋₆-alkoxy, more particularly a methoxy, C₁₋₆-fluoroalkyl,more particularly a CF₃; and/or

R₅ represents a hydrogen atom; and/or

R₆ represents a hydrogen atom or a C₁₋₆-alkyl group, more particularly amethyl.

Among the compounds of general formula (I), a third sub-group ofcompounds consists of compounds for which:

m represents an integer equal to 1 or 2; and/or

R₁ represents a group chosen especially from a phenyl, pyridyl,pyridazinyl, pyrimidinyl and thiadiazolyl, this group being optionallysubstituted with a group R₄; and/or

R₄ represents a group chosen especially from a phenyl, benzofuryl andnaphthyl; the group R₄ possibly being substituted with one or moregroups R₃, which may be identical or different, more particularly withone or two groups R₃, which may be identical or different; and/or

R₂ represents a group of general formula CHR₅CONHR_(6;) and/or

R₃ represents a halogen atom, more particularly a chlorine, a bromine ora fluorine, or a nitro group, C₁₋₆-alkyl, more particularly a methyl,isopropyl, C₁₋₆-alkoxy, more particularly a methoxy, ethoxy,C₁₋₆-fluoroalkyl, more particularly a CF₃, C₁₋₆-fluoroalkoxy, moreparticularly a OCF₃, —O—(C₁₋₃-alkylene)-O—, more particularly an—O—CH₂—O—, benzyloxy; and/or

R₅ represents a hydrogen atom; and/or

R₆ represents a hydrogen atom or a C₁₋₆-alkyl group, more particularly amethyl or an ethyl, or C₃₋₇-cycloalkyl-C₁₋₃-alkylene, more particularlya cyclopropyl-CH₂—.

Among the compounds of general formula (I), a fourth sub-group ofcompounds consists of compounds for which:

m is equal to 1; and/or

R₁ represents a group chosen especially from a phenyl, pyridyl,pyridazinyl and pyrimidinyl,

this group being optionally substituted with a group R₄; and/or

R₄ represents a group chosen especially from a phenyl, benzofuryl andnaphthyl; the group R₄ possibly being substituted with one or moregroups R₃, which may be identical or different, more particularly withone or two groups R₃, which may be identical or different; and/or

R₂ represents a group of general formula CHR₅CONHR_(6;) and/or

R₃ represents a halogen atom, more particularly a chlorine, a bromine ora fluorine, or a nitro group, C₁₋₆-alkyl, more particularly a methyl,isopropyl, C₁₋₆-alkoxy, more particularly a methoxy, ethoxy,C₁₋₆-fluoroalkyl, more particularly a CF₃, C₁₋₆-fluoroalkoxy, moreparticularly an OCF₃, —O—(C₁₋₃-alkylene)-O—, more particularly an—O—CH₂—O—, benzyloxy; and/or

R₅ represents a hydrogen atom; and/or

R₆ represents a hydrogen atom or a C₁₋₆-alkyl group, more particularly amethyl or an ethyl.

The compounds of general formula (I) may comprise one or more asymmetriccarbons. They may exist in the form of enantiomers and/ordiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures thereof, form part of theinvention.

The compounds of formula (I) may exist in the form of bases or ofacid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that are useful, for example for thepurification or isolation of the compounds of formula (I), also formpart of the invention.

The compounds of general formula (I) may be in the form of hydrates orof solvates, i.e. in the form of associations or combinations with oneor more water molecules or with a solvent. Such hydrates and solvatesalso form part of the invention.

In the context of the invention, the following definitions apply:

-   -   C_(t-z) in which t and z may take the values from 1 to 7, a        carbon-based chain possibly containing from t to z carbon atoms,        for example C₁₋₃ is a carbon-based chain which may contain from        1 to 3 carbon atoms,    -   alkyl, a saturated, linear or branched aliphatic group, for        example a C₁₋₃-alkyl group represents a linear or branched        carbon-based chain of 1 to 3 carbon atoms, more particularly a        methyl, ethyl, propyl or 1-methylethyl,    -   alkylene, a saturated, linear or branched divalent alkyl group,        for example a C₁₋₃-alkylene group represents a linear or        branched divalent carbon-based chain of 1 to 3 carbon atoms,        more particularly a methylene, ethylene, 1-methylethylene or        propylene,    -   cycloalkyl, a cyclic alkyl group, for example a C₃₋₅-cycloalkyl        group represents a cyclic carbon-based group of 3 to 5 carbon        atoms, more particularly a cyclopropyl, cyclobutyl or        cyclopentyl,    -   alkoxy, an —O-alkyl group containing a saturated, linear or        branched aliphatic chain,    -   thioalkyl, an —S-alkyl group containing a saturated, linear or        branched aliphatic chain,    -   fluoroalkyl, an alkyl group in which one or more hydrogen atoms        have been replaced with a fluorine atom,    -   fluoroalkoxy, an alkoxy group in which one or more hydrogen        atoms have been replaced with a fluorine atom,    -   fluorothioalkyl, a thioalkyl group in which one or more hydrogen        atoms have been replaced with a fluorine atom    -   halogen atom, a fluorine, a chlorine, a bromine or an iodine.

The compounds of the invention may be prepared according to variousmethods, illustrated by the schemes that follow.

Thus, a first preparation method (scheme 1) consists in reacting anamine of general formula (II), in which R₁ and m are as defined in thegeneral formula (I), with a carbonate of general formula (III), in whichZ represents a hydrogen atom or a nitro group and R₂ is as defined inthe general formula (I), in a solvent such as toluene or dichloroethane,at a temperature of between 0 and 80° C.

The carbonates of general formula (III) may be prepared according to anymethod described in the literature, for example by reacting an alcoholof general formula HOR₂ with phenyl chloroformate or 4-nitrophenylchloroformate, in the presence of a base such as triethylamine ordiisopropylethylamine, at a temperature of between 0° C. and the refluxtemperature of the solvent.

According to a second method (scheme 2), the compounds of generalformula (I) may be prepared by reacting an amine of general formula(II), as defined above, with a carbonate of general formula (IIIa) inwhich Z represents a hydrogen atom or a nitro group, R₅ is as defined inthe general formula (I) and R represents a methyl or ethyl group. Thecarbamate-ester of general formula (Ia) thus obtained is then convertedinto a compound of general formula (I), via aminolysis using an amine ofgeneral formula R₆NH₂ in which R₆ is as defined in the general formula(I). The aminolysis reaction may be performed in a solvent such asmethanol or a mixture of solvents such as methanol and tetrahydrofuranor methanol and dioxane.

The carbonates of general formula (IIIa) may be prepared according toany method described in the literature, for example by reacting analcohol of general formula HOCHR₅COOR in which R represents a methyl orethyl group, with phenyl chloroformate or 4-nitrophenyl chloroformate,in the presence of a base such as triethylamine ordiisopropylethylamine.

The compounds of general formula (I), in which R₁ represents a groupsubstituted with a group R₃ of C₁₋₆-alkyl, C₃₋₇-cycloalkyl orC₃₋₇-cycloalkyl-C₁₋₃-alkylene type, or with a group R₄ as defined in thegeneral formula (I), may also be prepared via a Suzuki reactionperformed on the corresponding compounds of general formula (I), forwhich R₁ is substituted with a chlorine, bromine or iodine atom or witha triflate group at the position in which the group R₃ or R₄ is to beintroduced, for example using an alkyl, cycloalkyl, aryl or heteroarylboronic acid.

For the compounds of general formula (I), in which R₁ represents a groupsubstituted with a group R₃ of C₁₋₆-alkyl, C₃₋₇-cycloalkyl orC₃₋₇-cycloalkyl-C₁₋₃-alkylene type or with a group R₄ as defined in thegeneral formula (I), and R₂ more particularly represents a group ofgeneral formula CHR₅CONHR₆, the Suzuki reaction described above may beperformed on the carbamate-ester of general formula (Ia) as definedabove. The action of an amine of general formula R₆NH₂ as defined aboveon the carbamate-ester thus obtained makes it possible to obtain thecompounds of general formula (I).

The compounds of general formula (II), when their mode of preparation isnot described, are commercially available or described in theliterature, or may even be prepared according to methods that aredescribed therein or that are known to those skilled in the art.

The amines of general formula R₆NH₂ are commercially available.

According to another of its aspects, a subject of the invention is alsothe compounds of formula (Ia). These compounds are useful asintermediates for synthesizing the compounds of formula (I).

The examples that follow illustrate the preparation of a number ofcompounds of the invention. These examples are not limiting and servemerely to illustrate the invention. The microanalyses and the IR and NMRand/or LC-MS (Liquid Chromatography coupled to Mass Spectroscopy)spectra confirm the structures and the purities of the compoundsobtained.

m.p. (° C.) represents the melting point in degrees Celsius. The numbersindicated in parentheses in the example titles correspond to those inthe first column of the table below:

EXAMPLE 1 (COMPOUND 44)

2-(methylamino)-2-oxoethyl4-{4′-[(trifluoromethyl)oxy]-4-biphenyl}-1-piperazinecarboxylate

1.1. ethyl [(phenyloxycarbonyl)oxy]acetate

32 ml (256 mmol) of phenyl chloroformate are added slowly at roomtemperature to a solution of 25 g (240 mmol) of ethyl glycolate and 55ml (315 mmol) of diisopropylethylamine in 500 ml of toluene. Stirring iscontinued at room temperature for 2 hours. The salt formed is separatedout and the filtrate is concentrated under reduced pressure. 53.7 g ofoily product are obtained, and are used without further purification inthe following step.

1.2. 2-(ethyloxy)-2-oxoethyl 4-(4-bromophenyl)-1-piperazinecarboxylate

A solution of 5.81 g (24.08 mmol) of 1-(4-bromophenyl)piperazine and 6 g(26.76 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, obtained in step1.1., in 50 ml of toluene, is heated at 80° C. for 12 hours.

The mixture is allowed to cool to room temperature, it is concentratedunder reduced pressure and the residue thus obtained is then purified bychromatography on silica gel, eluting with a 20/80 and then 30/70mixture of ethyl acetate and cyclohexane. 7.75 g of pure product in theform of an oil that crystallizes at room temperature are thus obtained.

m.p. (° C.): 80-82° C.

1.3. 2-(ethyloxy)-2-oxoethyl4-{4′-(trifluoromethyl)oxy]-4-biphenylyl}-1-piperazinecarboxylate

2 g (5.39 mmol) of 2-(ethyloxy)-2-oxoethyl4-(4-bromophenyl)-1-piperazinecarboxylate, obtained in step 1.2., 3.33 g(16.16 mmol) of 4-(trifluoromethoxy)phenylboronic acid and 4.57 g (21.55mmol) of hydrated potassium phosphate suspended in 18 ml of1,2-dimethoxyethane are introduced, under an inert atmosphere. 0.62 g(0.54 mmol) of tetrakis(triphenylphosphine)palladium is then added. Thereaction mixture is then maintained at about 80° C. for 12 hours. It isconcentrated under reduced pressure. The residue is taken up withdichloromethane and water, the aqueous phase is separated out andextracted twice with dichloromethane, the combined organic phases aredried over sodium sulfate and the filtrate is concentrated under reducedpressure. The residue thus obtained is purified by chromatography onsilica gel, eluting with a 30/70 mixture of ethyl acetate andcyclohexane. 1.65 g of product are obtained in the form of a whitesolid.

m.p. (° C.): 112-116° C.

1.4. 2-(methylamino)-2-oxoethyl4-{4′-[(trifluoromethyl)oxy]-4-biphenylyl}-1-piperazinecarboxylate

7.10 ml (14.15 mmol) of a solution of methylamine (2M) intetrahydrofuran are added to a solution of 1.60 g (3.54 mmol) of2-(ethyloxy)-2-oxoethyl4-{4′-[(trifluoromethyl)oxy]-4-biphenylyl}-1-piperazinecarboxylate,prepared in step 1.3., in 14 ml of methanol. Stirring is continued atroom temperature for 12 hours. After concentrating under reducedpressure, the residue obtained is purified by chromatography on silicagel, eluting with a 97/3 mixture of dichloromethane and methanol. Asolid is obtained, and is recrystallized from a mixture of ethyl acetateand diisopropyl ether. 0.86 g of pure product is thus obtained in theform of a white solid.

LC-MS: M+H=438

m.p. (° C.): 187-189° C.

¹H NMR (CDCl₃) δ (ppm): 2.90 (d, 3H); 3.25 (m, 4H); 3.70 (m, 4H) ; 4.60(s, 2H) ; 6.10 (broad s, 1H) ; 7.0 (d, 2H) ; 7.30 (d, 2H) ; 7.50 (d, 2H); 7.60 (d, 2H).

EXAMPLE 2 (COMPOUND 37)

2-(methylamino)-2-oxoethyl4-[3′-(trifluoromethyl)-4-biphenylyl]-1-piperazinecarboxylate

2.1. 2-(methylamino)-2-oxoethyl 4-nitrophenyl carbonate

5.93 g (29.4 mmol) of 4-nitrophenyl chloroformate are added portionwiseand at room temperature to a suspension of 2.62 g (29.4 mmol) of2-hydroxy-N-methylacetamide and 16.5 g (58.7 mmol) of supporteddiisopropylethylamine (Ps-DIEA from Argonaut, charge=3.56 mmol/g) in 250ml of dichloromethane. Orbital stirring is continued at room temperaturefor 16 hours. The resin is filtered off and rinsed with 150 ml ofdichloromethane, and the filtrate is concentrated under reducedpressure. 6 g of product are obtained in the form of a pale yellow solid(purity estimated at 70%), and are used without further purification inthe following step.

2.2. 2-(methylamino) -2-oxoethyl4-(4-bromophenyl)-1-piperazinecarboxylate

1.17 g (4.85 mmol) of 1-(4-bromophenyl)piperazine are added to asolution of 1.47 g (4 mmol) of 2-(methylamino)-2-oxoethyl 4-nitrophenylcarbonate, obtained in step 2.1., in 18 ml of 1,2-dichloroethane. Thisreaction mixture is heated at 65° C. for 2.25 hours. The mixture isallowed to cool to room temperature and it is then concentrated underreduced pressure. The oily yellow residue is taken up in dichloromethaneand washed successively with sodium hydroxide (1N), water, aqueous 5%citric acid solution, water and then brine. This organic phase is driedover sodium sulfate and is concentrated under reduced pressure. Afterwashing with diisopropyl ether, 1.3 g of product are obtained in theform of a white solid.

2.3. Synthesis of the Palladium Catalyst Grafted onto Merrifield Resin

54.6 ml (27.3 mmol) of a solution of lithium diphenylphosphide, sold at0.5 M in THF under an inert atmosphere, are introduced into a suspensionof 5 g (3.5 mmol) of Merrifield resin (Fluka, 200-400 Mesh, crosslinkedwith 2% of divinylbenzene (DVB), Charge=0.7 mmol/g) in 50 ml ofanhydrous tetrahydrofuran (THF). Orbital stirring is continued at roomtemperature for 24 hours, and 60 ml of acetone and 20 ml of water arethen added. The resin is filtered off and is washed successively withwater, acetone, THF, a THF/H₂O (2/1) mixture, THF, toluene,dichloromethane and ethyl ether and is then dried under vacuum for 2hours. A suspension of the resin thus obtained is maintained at 70° C.for 24 hours in 47 ml of ethanol and 23 ml of toluene. After filtration,the resin is washed successively with acetone, THF and ethyl ether. Intotal, this treatment is repeated four times to remove the solublefractions of the polymer. The resin thus obtained is dried under vacuumfor 2 hours. 0.18 g (0.16 mmol) of tetrakis(triphenylphosphine)palladiumis added to a suspension of this resin in 60 ml of toluene and thisreaction mixture is maintained at 95° C. for 24 hours. The mixture isallowed to cool to room temperature, and the resin is filtered off andwashed successively with acetone, THF and then ethyl ether. 5.135 g ofresin are obtained, and are used without further purification in thefollowing step.

2.4. 2-(methylamino)-2-oxoethyl4-[3′-(trifluoromethyl)-4-biphenylyl]-1-piperazinecarboxylate

0.18 g (0.5 mmol) of 2-(methylamino)-2-oxoethyl4-(4-bromophenyl)-1-piperazinecarboxylate, obtained in step 2.2., 0.21 g(1.1 mmol) of 3-(trifluoromethyl)phenylboronic acid and 0.16 g (1.5mmol) of sodium carbonate suspended in 3 ml of toluene and 0.3 ml ofethanol are introduced. 0.14 g (˜10 mol %) of supported palladiumcatalyst, obtained in step 2.3., are then added and orbital stirring iscontinued at 80° C. for 48 hours. The mixture is allowed to cool to roomtemperature, the resin is filtered off and rinsed with dichloromethane,and the filtrate is concentrated under reduced pressure. The residue istaken up in 5 ml of dichloromethane and washed with water and then withsaturated aqueous sodium bicarbonate solution. The organic phase isfiltered through a hydrophobic cartridge and the filtrate is thenconcentrated under reduced pressure. An oily residue that crystallizesfrom diisopropyl ether is obtained. 0.15 g of white crystals isobtained.

LC-MS: M+H=422

m.p. (° C.): 129-130° C.

¹H NMR (CDCl₃) δ (ppm): 2.95 (d, 3H); 3.20-3.35 (m, 4H); 3.65-3.80 (m,4H); 4.65 (s, 2H); 6.05 (broad s, 1H); 7.05 (d, 2H); 7.50-7.60 (m, 4H);7.65-7.80 (m, 2H)

EXAMPLE 3 (COMPOUND 76)

2-(methylamino)-2-oxoethyl4-{5-[3-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate

3.1. 1,1-dimethylethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate

29.2 g (157 mmol) of 1,1-dimethylethyl 1-piperazinecarboxylate, 37 g(157 mmol) of 2,5-dibromopyridine and 21.7 g (157 mmol) of potassiumcarbonate suspended in 27 ml of dimethyl sulfoxide (DMSO) are introducedinto an autoclave. The mixture is then heated at 150° C. for 21 hours.The reaction mixture is allowed to cool to room temperature, it is takenup in ethyl acetate and water and the insoluble material is thenseparated out by filtration. The aqueous phase is separated out andextracted twice with ethyl acetate, the combined organic phases arewashed with saturated aqueous sodium chloride solution and dried oversodium sulfate, and the filtrate is concentrated under reduced pressure.The residue obtained is purified by chromatography on silica gel,eluting with a 99/1 mixture of dichloromethane and methanol. 44 g ofproduct are thus obtained in the form of a white solid.

m.p. (° C.): 83-85° C.

3.2. 1-(5-bromo-2-pyridyl)piperazine

49 ml (272 mmol) of a solution of hydrochloric acid (6N) in isopropanolare added at room temperature to a solution of 18.60 g (54.40 mmol) of1,1-dimethylethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate,obtained in step 3.1., in 100 ml of 1.4-dioxane. The reaction mixture isthen maintained at about 60° C. for 3 hours. The mixture is concentratedto dryness under reduced pressure. The dihydrochloride obtained is takenup in 200 ml of dichloromethane and 200 ml of water, followed byportionwise addition, with stirring, of 10 g of sodium hydrogencarbonate. The phases are separated by settling, the aqueous phase isextracted twice with dichloromethane, and the combined organic phasesare washed with saturated aqueous sodium chloride solution, dried oversodium sulfate and concentrated under reduced pressure. 12 g of productare obtained in the form of a white solid.

m.p. (° C.): 72° C. 3.3. 2-(ethyloxy)-2-oxoethyl4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate

The process is performed as described in Example 1 (step 1.2.). Startingwith 6 g (24.80 mmol) of 1-(5-bromo-2-pyridyl)piperazine, obtained instep 3.2., and 10.88 g (48.52 mmol) of ethyl[(phenyloxycarbonyl)oxy]acetate, prepared in step 1.1. of Example 1, andafter chromatography on silica gel, eluting with a 15/85 and then 30/70mixture of ethyl acetate and cyclohexane, 6.70 g of product are obtainedin the form of an oil that crystallizes to a white solid.

3.4. 2-(ethyloxy)-2-oxoethyl4-{5-[3-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate

The process is performed according to the procedure described in Example1 (step 1.3.). Starting with 3 g (8.06 mmol) of 2-(ethyloxy)-2-oxoethyl4-(5-bromo-2-pyridyl)-1-piperazine-carboxylate, obtained in step 3.3.,4.59 g (24.17 mmol) of 3-(trifluoromethyl)phenylboronic acid, 6.84 g(32.23 mmol) of hydrated potassium phosphate and 0.93 g (0.806 mmol) oftetrakis(triphenylphosphine)palladium, and after chromatography onsilica gel, eluting with a 30/70 mixture of ethyl acetate andcyclohexane, 2.22 g of product are obtained in the form of a whitesolid.

3.5. 2-(methylamino)-2-oxoethyl4-{5-[3-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate

The process is performed according to the procedure described in Example1 (step 1.4.). Starting with 1.50 g (3.43 mmol) of2-(ethyloxy)-2-oxoethyl4-{5-[3-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate,obtained in step 3.4., and 8.6 ml (17.15 mmol) of a solution ofmethylamine (2M) in tetrahydrofuran, and after chromatography on silicagel, eluting with a 97/3 mixture of dichloromethane and methanol,followed by washing with diisopropyl ether, 1.18 g of product areobtained in the form of a white solid.

LC-MS: M+H=423

m.p. (° C.): 158-160° C.

¹H NMR (CDCl₃) δ (ppm): 2.90 (d, 3H); 3.75 (broad s, 8H); 4.65 (s, 2H);6.05 (broad s, 1H); 6.75 (d, 1H); 7.50-7.80 (multiplet, 5H); 8.50 (d,1H).

EXAMPLE 4 (COMPOUND 79)

2-(methylamino)-2-oxoethyl4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate

4.1. 2-(ethyloxy)-2-oxoethyl4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate

The process is performed according to the procedure described in Example1 (step 1.3.). Starting with 4 g (10.75 mmol) of 2-(ethyloxy)-2-oxoethyl4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. ofExample 3, 5.50 g (28.96 mmol) of 4-(trifluoromethyl)phenylboronic acid,9.12 g (42.99 mmol) of hydrated potassium phosphate and 1.24 g (1.07mmol) of tetrakis(triphenylphosphine)palladium, and after chromatographyon silica gel, eluting with a 30/70 mixture of ethyl acetate andcyclohexane, 2.78 g of product are obtained in the form of a whitesolid.

4.2. 2-(methylamino)-2-oxoethyl4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate

The process is performed according to the procedure described in Example1 (step 1.4.). Starting with 2.77 g (6.33 mmol) of2-(ethyloxy)-2-oxoethyl4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate,obtained in step 4.1., and 15.80 ml (31.67 mmol) of a solution ofmethylamine (2M) in tetrahydrofuran, and after chromatography on silicagel, eluting with a 97/3 mixture of dichloromethane and methanol,followed by recrystallization from ethyl acetate, 1.69 g of product areobtained in the form of a white solid.

LC-MS: M+H=423

m.p. (° C.): 206-209° C.

¹H NMR (CDCl₃) δ (ppm): 2.90 (d, 3H); 3.70 (broad s, 8H); 4.65 (s, 2H);6.05 (broad s, 1H); 6.75 (d, 1H); 7.60-7.75 (m, 4H); 7.80 (dd, 1H); 8.50(d, 1H).

EXAMPLE 5 (COMPOUND 83)

2-(methylamino)-2-oxoethyl4-(5-{4-[(trifluoromethyl)oxy]phenyl}-2-pyridyl)-1-piperazinecarboxylate

5.1. 1,1-dimethylethyl 2-(methylamino)-2-oxoethyl1,4-piperazinedicarboxylate

A solution of 0.53 g (2.85 mmol) of 1,1-dimethylethyl1-piperazinecarboxylate in 5 ml of 1,2-dichloroethane is added dropwiseat about 0° C. to a solution, cooled to 0° C., of 1.1 g (3 mmol) of2-(methylamino)-2-oxoethyl 4-nitrophenyl carbonate, prepared in step2.2. of Example 2, in 10 ml of 1,2-dichloroethane. Stirring is continuedat 0° C. for 1 hour, and then at room temperature for 3 hours. Thereaction mixture is concentrated under reduced pressure and the residuethus obtained is purified by chromatography on silica gel, eluting witha 20/80 mixture of ethyl acetate and cyclohexane. The gradient isgradually increased to complete the elution with ethyl acetate. An oilyresidue that crystallizes from diisopropyl ether is obtained. 0.61 g ofproduct is obtained in the form of a white solid, and is used withoutfurther purification in the following step.

5.2. 2-(methylamino)-2-oxoethyl 1-piperazinecarboxylate hydrochloride

25 ml of a 6N solution of hydrogen chloride in isopropanol are added toa solution of 2.68 g (8.9 mmol) of 2-(methylamino)-2-oxoethyl1,1-dimethylethyl-1,4-piperazinedicarboxylate, obtained according tostep 5.1., in 25 ml of dichloromethane. Stirring is continued at roomtemperature for 1 hour. The organic phase is removed by filtrationthrough a hydrophobic cartridge and the acidic aqueous phase isconcentrated under reduced pressure. After crystallization fromisopropanol, 2.05 g of product are obtained in the form of a whitesolid, and are used without further purification in the following step.

m.p. (° C.): 167-169° C.

5.3. 2-(methylamino)-2-oxoethyl4-(5-nitro-2-pyridyl)-1-piperazinecarboxylate

1.84 g (11.6 mmol) of 2-chloro-5-nitropyridine are added to a solutionof 2.05 g (8.62 mmol) of 2-(methylamino)-2-oxoethyl1-piperazinecarboxylate hydrochloride, obtained in step 5.2., and 3.85ml (22.4 mmol) of N,N diisopropylethylamine in 55 ml of1,2-dichloroethane. This reaction mixture is maintained at 70° C. for 5hours. The mixture is allowed to cool to room temperature andconcentrated under reduced pressure, and the residue thus obtained ispurified by chromatography on silica gel, eluting with a 98/2 mixture ofdichloromethane and methanol. 2.48 g of product are obtained in the formof a pale yellow solid, and are used without further purification in thefollowing step.

5.4. 2-(methylamino)-2-oxoethyl4-(5-amino-2-pyridyl)-1-piperazinecarboxylate

0.24 g of 10% palladium on charcoal is added to a suspension of 0.64 g(1.98 mmol) of 2-(methylamino)-2-oxoethyl4-(5-nitro-2-pyridyl)-1-piperazinecarboxylate, prepared in step 5.3., in90 ml of ethyl acetate. Stirring is continued at room temperature undera hydrogen atmosphere of 60 psi for 14 hours. After filtering off thecatalyst, the filtrate is concentrated under reduced pressure and theresidue thus obtained is purified by chromatography on silica gel,eluting with a 98/2 mixture of dichloromethane and methanol. 0.47 g ofproduct is obtained in the form of a violet-colored oil, and is usedwithout further purification in the following step.

5.5. 2-(methylamino)-2-oxoethyl4-(5-iodo-2-pyridyl)-1-piperazinecarboxylate

A solution of 0.16 g (2.2 mmol) of sodium nitrite dissolved in 3.5 ml ofwater is slowly added to a solution, cooled to 0° C., of 0.47 g (1.5mmol) of 2-(methylamino)-2-oxoethyl4-(5-amino-2-pyridyl)-1-piperazinecarboxylate, prepared in step 5.4., in15 ml of aqueous sulfuric acid solution (0.33N). Stirring is continuedat about 0° C. for half an hour, and 0.83 g (5 mmol) of potassium iodideis slowly added. Stirring is continued at this temperature for half anhour and the reaction mixture is then maintained at 85° C. for 2 hours.After cooling to room temperature, the reaction medium is basified topH=14, by adding saturated aqueous sodium bicarbonate solution. Theaqueous phase is extracted three times with dichloromethane, thecombined organic phases are washed with aqueous 35% thiosulfitesolution, water, brine and dried over sodium sulfate. The filtrate isconcentrated under reduced pressure and the residue thus obtained ispurified by chromatography on silica gel, eluting with a 98/2 mixture ofdichloromethane and methanol. After washing with diisopropyl ether, 0.35g of product is obtained in the form of a beige-colored solid, and isused without further purification in the following step.

5.6. 2-(methylamino)-2-oxoethyl4-(5-{4-[(trifluoromethyl)oxy]phenyl}-2-pyridyl)-1-piperazinecarboxylate

The process is performed according to the procedure described in Example2 (step 2.4.). Starting with 0.250 g (0.61 mmol) of2-(methylamino)-2-oxoethyl 4-(5-iodo-2-pyridyl)-1-piperazinecarboxylate,obtained in step 5.5., 0.51 g (2.44 moles) of4-(trifluoromethoxy)phenylboronic acid, 0.61 g (˜8 mol %) of palladiumcatalyst on a solid support, prepared in step 2.1. of Example 2, and 2.9ml (7.32 mmol) of aqueous sodium carbonate solution (2.5M) suspended in12 ml of toluene and 3 ml of ethanol, and after chromatography on silicagel, eluting with a 98/2 mixture of dichloromethane and methanol,followed by washing with diisopropyl ether, 0.092 g of product isobtained in the form of a white solid.

LC-MS: M+H=439

m.p. (° C.): 188-190° C.

¹H NMR (CDCl₃) (ppm): 2.90 (d, 3H); 4.70 (broad s, 8H); 4.65 (s, 2H) ;6.05 (broad s, 1H) ; 6.75 (dd, 1H) ; 7.30 (d, 2H); 7.55 (d, 2H); 7.75(dd, 1H); 8.45 (dd, 1H).

EXAMPLE 6 (COMPOUND 63)

2-(methylamino)-2-oxoethyl4-[5-(2-methylpropyl)-2-pyridyl]-1-piperazinecarboxylate

6.1. 2-(methylamino)-2-oxoethyl4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate

The process is performed as described in Example 1 (step 1.4.). Startingwith 2.20 g (5.91 mmol) of 2-(ethyloxy)-2-oxoethyl4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. ofExample 3, and 14.80 ml (29.55 mmol) of a solution of methylamine (2M)in tetrahydrofuran, and after crystallization from diisopropyl ether,1.974 g of pure product are obtained in the form of a white solid.

6.2. 2-(methylamino)-2-oxoethyl4-[5-(2-methylpropyl)-2-pyridyl]-1-piperazinecarboxylate

0.88 g (2.47 mmol) of 2-(methylamino)-2-oxoethyl4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 6.1.,0.33 g (3.22 mmol) of isobutylboronic acid, 1.16 g (5.44 mmol) ofhydrated potassium phosphate and 0.07 g (0.25 mmol) oftricyclohexylphosphine suspended in 11 ml of toluene are placed togetherunder an inert atmosphere. 0.028 g (0.12 mmol) of palladium diacetate isthen added. The reaction mixture is then refluxed for 3 hours. Themixture is allowed to cool to room temperature and 15 ml of water and 15ml of ethyl acetate are then added. The salts are separated out byfiltration through a sinter, the phases are separated by settling, theaqueous phase is extracted twice with ethyl acetate, and the combinedorganic phases are washed with saturated aqueous sodium chloridesolution and dried over sodium sulfate. After evaporating off thesolvent, the residue obtained is purified by chromatography on silicagel, eluting with a 97/3 mixture of dichloromethane and methanol. Aftercrystallization from diisopropyl ether, 0.17 g of product is obtained inthe form of a white solid.

LC-MS: M+H=335

m.p. (° C.): 127-129° C.

¹H NMR (CDCl₃) δ (ppm): 0.90 (d, 6H); 1.80 (m, 1H); 2.35 (d, 2H) ; 2.90(d, 3H) ; 3.60 (m, 8H) ; 4.65 (s, 2H) ; 6.10 (broad s, 1H) ; 6.60 (d,1H) ; 7.35 (dd, 1H) ; 8.0 (d, 1H).

EXAMPLE 7 (COMPOUND 85)

2-(methylamino)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate

7.1. 1,1-dimethylethyl 4-(3-pyridyl)-1-piperazinecarboxylate

7.07 g (44.74 mmol) of 3-bromopyridine, 10 g (53.69 mmol) of1,1-dimethylethyl 1-piperazinecarboxylate, 6.02 g (62.64 mmol) of sodiumtert-butoxide and 0.836 g (1.34 mmol) of(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP) suspended in 100ml of toluene are introduced under an inert atmosphere. 0.41 g (0.45mmol) of [tris(dibenzylideneacetone)dipalladium] (Pd₂(dba)₃) is thenadded. The reaction mixture is then refluxed for 22 hours. The mixtureis allowed to cool to room temperature, the salts are separated out byfiltration through glass fiber and the filtrate is then concentratedunder reduced pressure. The residue is taken up in 100 ml of ethylacetate and 100 ml of water, the aqueous phase is separated out andextracted several times with ethyl acetate, the combined organic phasesare washed with saturated aqueous sodium chloride solution and driedover sodium sulfate, and the filtrate is concentrated under reducedpressure. The residue thus obtained is purified by chromatography onsilica gel, eluting with a 98/2 and then 95/5 mixture of dichloromethaneand methanol. 9.80 g of product are obtained in the form of an oil thatcrystallizes at room temperature.

7.2. 1,1-dimethylethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate

2.70 g (15.19 mmol) of N-bromosuccinimide (NBS) are added portionwise toa solution of 4 g (15.19 mmol) of 1,1-dimethylethyl4-(3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.1., in 50 mlof acetonitrile, cooled to about 0° C. Stirring is continued at 0° C.for 15 minutes and then at room temperature for 2 hours. 100 ml ofaqueous sodium hydroxide solution (1M) and 100 ml of ethyl acetate areadded to the reaction medium. The aqueous phase is separated out andextracted twice with ethyl acetate, the combined organic phases arewashed with saturated aqueous sodium chloride solution and dried oversodium sulfate, and the filtrate is concentrated under reduced pressure.5.16 g of product are thus obtained in the form of an orange-yellowsolid, and are used without further purification in the following step.

7.3. 1-(6-bromo-3-pyridyl)piperazine

11.20 ml (150.77 mmol) of trifluoroacetic acid are slowly added to asuspension of 5.16 g (15.08 mmol) of 1,1-dimethylethyl4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.2., in70 ml of dichloromethane. Stirring is continued at room temperature for16 hours. The reaction mixture is concentrated under reduced pressure,the residue is taken up in 40 ml of chloroform and 4 ml of aqueoussodium hydroxide solution (10M) are then slowly added. The aqueous phaseis separated out and then extracted twice with chloroform. The organicphases are combined and are washed with saturated aqueous sodiumchloride solution. The organic phase is dried over sodium sulfate andthe filtrate is concentrated under reduced pressure. 5.16 g of productare thus obtained in the form of an orange-colored oil that crystallizesat room temperature. This product is used without further purificationin the following step.

7.4. 2-(ethyloxy)-2-oxoethyl4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate

The process is performed as described in Example 1 (step 1.2.). Startingwith 3.57 g (14.76 mmol) of 1-(6-bromo-3-pyridyl)piperazine, obtained instep 7.3., and 3.97 g (17.71 mmol) of ethyl[(phenyloxycarbonyl)oxy]acetate, prepared in step 1.1. of Example 1, andafter chromatography on silica gel, eluting with a 99/1 and then 98/2mixture of dichloromethane and methanol, 3.75 g of product are obtainedin the form of a yellow oil that crystallizes at room temperature.

7.5. 2-(ethyloxy)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate

The process is performed according to the procedure described in Example1 (step 1.3.). Starting with 1.28 g (3.43 mmol) of2-(ethyloxy)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate,obtained in step 7.4., 1.96 g (10.29 mmol) of3-(trifluoromethyl)phenylboronic acid, 2.91 g (13.72 mmol) of hydratedpotassium phosphate and 0.40 g (0.34 mmol) oftetrakis(triphenylphosphine)palladium, and after chromatography onsilica gel, eluting with a mixture 35/65 of ethyl acetate andcyclohexane, 0.98 g of pure product is obtained in the form of an oilthat crystallizes at room temperature.

7.6. 2-(methylamino)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate

The procedure described in Example 1 (step 1.4.) is used. Starting with0.60 g (1.37 mmol) of 2-(ethyloxy)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate,obtained in step 7.5., and 3.40 ml (6.86 mmol) of a solution ofmethylamine (2M) in tetrahydrofuran, and after chromatography on silicagel, eluting with a 98/2 and then 97/3 mixture of dichloromethane andmethanol, followed by washing with diisopropyl ether, 0.36 g of pureproduct is obtained in the form of a white solid.

LC-MS: M+H=423

m.p. (° C.): 146-150° C.

¹H NMR (CDCl₃) δ (ppm): 2.90 (d, 3H); 3.35 (m, 4H); 3.80 (m, 4H); 4.65(s, 2H); 6.05 (broad s, 1H); 7.30 (m, 1H); 7.65 (m, 2H) ; 7.70 (d, 1H) ;8.10 (d, 1H) ; 8.25 (s, 1H) ; 8.45 (d, 1H).

EXAMPLE 8 (COMPOUND 86)

2-amino-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate

5.90 ml (41.40 mmol) of a solution of ammonia (7N) in methanol are addedto a solution of 0.30 g (0.69 mmol) of 2-(ethyloxy)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate,obtained in step 7.5. of Example 7, in 6 ml of a 1/1 mixture of methanoland tetrahydrofuran. Stirring is continued at room temperature for 22hours. After concentrating under reduced pressure, the residue obtainedis purified by chromatography on silica gel, eluting with a 96/4 mixtureof dichloromethane and methanol, followed by washing with diisopropylether. 0.19 g of pure product is obtained in the form of a yellow solid.

LC-MS: M+H=409

m.p. (° C.): 155-157° C.

¹H NMR (CDCl₃) δ (ppm): 3.35 (m, 4H); 3.75 (m, 4H); 4.70 (s, 2H); 5.50(broad s, 1H); 6.0 (broad s, 1H); 7.30 (m, 1H) ; 7.55 (m, 2H) ; 7.70 (d,1H) ; 8.10 (d, 1H) ; 8.25 (s, 1H) ; 8.40 (d, 1H).

EXAMPLE 9 (COMPOUND 66)

2-(methylamino)-2-oxoethyl4-[6-(2-methylpropyl)-3-pyridyl]-1-piperazinecarboxylate

9.1. 2-(methylamino)-2-oxoethyl4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate

The procedure described in Example 1 (step 1.4.) is used. Starting with2.35 g (6.32 mmol) of 2-(ethyloxy)-2-oxoethyl4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.4. ofExample 7, and 15.80 ml (31.61 mmol) of a solution of methylamine (2M)in tetrahydrofuran, and after chromatography on silica gel, eluting witha 98/2 and then 97/3 mixture of dichloromethane and methanol, 1.779 g ofproduct are obtained in the form of a white solid.

m.p. (° C.): 164° C.

9.2. 2-(methylamino)-2-oxoethyl4-[6-(2-methylpropyl)-3-pyridyl]-1-piperazinecarboxylate

1.25 g (3.50 mmol) of 2-(methylamino)-2-oxoethyl4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, prepared in step 9.1.,and 0.12 g (0.17 mmol) of dichlorobis(triphenylphosphine)palladium(Pd(PPh₃)₂Cl₂) suspended in 7 ml of tetrahydrofuran are introduced underan inert atmosphere. 17.50 ml (8.74 mmol) of a solution ofbromoisobutylzinc (0.5M) in tetrahydrofuran are then added. Stirring iscontinued at room temperature for 19 hours. The reaction mixture ispoured into 25 ml of water and 25 ml of ethyl acetate. The insolublematerial is filtered off through glass fiber. The phases are separatedby settling, the aqueous phase is extracted twice with ethyl acetate,the combined organic phases are dried over sodium sulfate and thefiltrate is concentrated under reduced pressure. The residue thusobtained is purified by chromatography on silica gel, eluting with a95/5 mixture of dichloromethane and methanol, followed bycrystallization from diisopropyl ether. 0.36 g of product is obtained inthe form of a brown solid.

LC-MS: M+H=335

m.p. (° C.): 87-89° C.

¹H NMR (CDCl₃) δ (ppm): 0.90 (d, 6H); 2.05 (m, 1H); 2.60 (d, 2H) ; 2.90(d, 3H) ; 3.20 (m, 4H) ; 3.70 (m, 4H) ; 4.65 (s, 2H); 6.05 (broad s,1H); 7.0-7.20 (m, 2H); 8.25 (d, 1H).

EXAMPLE 10 (COMPOUND 87)

2-(methylamino)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate

10.1. 2-(ethyloxy)-2-oxoethyl4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate

The process is performed as described in Example 1 (step 1.2.). Startingwith 1.60 g (8.05 mmol) of 3-chloro-6-(1-piperazinyl)pyridazine (J. Med.Chem., 18, 2002, 4011-4017) and 1.99 g (8.86 mmol) of ethyl[(phenyloxycarbonyl)oxy]acetate, prepared in step 1.1. of Example 1, andafter chromatography on silica gel, eluting with a 98/2 mixture ofdichloromethane and methanol, 1.70 g of product are obtained in the formof a white solid.

m.p. (° C.): 149-151° C.

10.2. 2-(ethyloxy)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate

The process is performed according to the procedure described in Example1 (step 1.3.). Starting with 1.15 g (3.50 mmol) of2-(ethyloxy)-2-oxoethyl4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate, obtained in step10.1., 1.99 g (10.49 mmol) of 3-(trifluoromethyl)phenylboronic acid,2.97 g (13.99 mmol) of hydrated potassium phosphate and 0.40 g (0.35mmol) of tetrakis(triphenylphosphine)palladium, and after chromatographyon silica gel, eluting with a 35/65 and then 45/55 mixture of ethylacetate and cyclohexane, 0.67 g of pure product is obtained in the formof a solid.

m.p. (° C.): 126-128° C.

10.3. 2-(methylamino)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate

The procedure described in Example 1 (step 1.4.) is used. Starting with0.66 g (1.51 mmol) of 2-(ethyloxy)-2-oxoethyl4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate,obtained in step 10.2., and 3 ml (6.02 mmol) of a solution ofmethylamine (2M) in tetrahydrofuran, and after chromatography on silicagel, eluting with a 96/4 mixture of dichloromethane and methanol,followed by washing with diisopropyl ether, 0.50 g of product isobtained in the form of a white solid.

LC-MS: M+H=424

m.p. (° C.): 151-153° C.

¹H NMR (DMSO) δ (ppm): 2.60 (d, 3H); 3.55 (m, 4H); 3.75 (m, 4H) ; 4.45(s, 2H) ; 7.40 (d, 1H) ; 7.80 (m, 3H) ; 8.10 (d, 1H) ; 8.35 (m, 2H).

EXAMPLE 11 (COMPOUND 103)

2-(methylamino)-2-oxoethyl4-(5-{4-[(trifluoromethyl)oxy]phenyl}-2-pyridyl)-1,4-diazepane-1-carboxylate

11.1. 1,1-dimethylethyl4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate

1.03 g (5 mmol) of 1,1-dimethylethyl 1,4-diazepane-1-carboxylate, 1.19 g(5 mmol) of 2,5-dibromopyridine and 0.7 g (5 mmol) of potassiumcarbonate suspended in 0.90 ml of dimethyl sulfoxide (DMSO) areintroduced into an autoclave. The mixture is heated at 150° C. for 22hours. The reaction mixture is allowed to cool to room temperature, itis taken up in ethyl acetate, and the organic solution is washed withwater and then brine, and dried over sodium sulfate. The filtrate isconcentrated under reduced pressure and the residue thus obtained ispurified by chromatography on silica gel, eluting with a 99.5/0.5mixture of dichloromethane and methanol. 1.63 g of product are obtainedin the form of an oil, and are used without further purification in thefollowing step.

11.2. 1-(5-bromo-2-pyridyl)-1,4-diazepane

6 ml of a solution of hydrogen chloride (6N) in isopropanol are added toa solution of 1.63 g (4.4 mmol) of 1,1-dimethylethyl4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate, obtained in step11.1., in 12 ml of dioxane and 4 ml of ethanol. This reaction mixture ismaintained at 70° C. for 3 hours. The mixture is allowed to cool to roomtemperature and is then concentrated under reduced pressure. 1.32 g of awhite solid are obtained after crystallization from acetone. Thesecrystals are taken up in 10 ml of dichloromethane and the reactionmedium is basified to pH=14, by adding 28% ammonia solution. The organicphase is recovered by filtration through a hydrophobic cartridge and thefiltrate is concentrated under reduced pressure. 0.96 g of product isobtained in the form of an oil, and is used without further purificationin the following step.

11.3. 2-(methylamino)-2-oxoethyl4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate

The process is performed as described in Example 1 (step 1.2.). Startingwith 0.95 g (3.70 mmol) of 1-(5-bromo-2-pyridyl)-1,4-diazepane, obtainedin step 11.2., and 0.94 g (3.70 mmol) of 2-(methylamino)-2-oxoethyl4-nitrophenyl carbonate, prepared in step 2.2. of Example 2, and afterchromatography on silica gel, eluting with a 30/70 mixture of ethylacetate and cyclohexane and then with a 95/5 mixture of dichloromethaneand methanol, followed by crystallization from diisopropyl ether, 0.97 gof product is obtained in the form of a white solid.

11.4. 2-(methylamino)-2-oxoethyl4-(5-{4-[(trifluoromethyl)oxy]phenyl}-2-pyridyl)-1,4-diazepane-1-carboxylate0.12 g (0.3 mmol) of 2-(methylamino)-2-oxoethyl4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate, prepared in step11.3., 0.25 g (1.2 mmol) of 4-(trifluoromethoxy)phenylboronic acid and0.9 ml (1.8 mmol) of aqueous sodium carbonate solution (2M), suspendedin 3.5 ml of toluene and 0.8 ml of ethanol are introduced into a Pyrexreactor. 0.07 g (0.06 mmol) of tetrakis(triphenylphosphine)palladium isthen added and, after sealing the reactor, it is maintained at 150° C.for 15 minutes under microwave irradiation. The organic phase isrecovered after separation of the phases by settling, and the filtrateis concentrated under reduced pressure. The residue thus obtained ispurified by chromatography on silica gel, eluting with a 30/70/5 mixtureof ethyl acetate, cyclohexane and methanol. After crystallization fromdiisopropyl ether, 0.078 g of product is obtained in the form of a whitesolid.

LC-MS: M+H=452

m.p. (° C.): 191-193° C.

¹H NMR (DMSO) (ppm): 1.70-2.00 (m, 2H); 2.55 (d, 3H); 3.25-3.40 (m, 2H);3.40-3.90 (m, 6H); 4.35 (d, 2H); 6.75 (d, 1H); 7.35 (d, 2H); 7.70 (broadd, 2H+NH); 7.80 (dd, 1H) ; 8.45 (d, 1H).

Table 1 below illustrates the chemical structures and the physicalproperties of a number of compounds according to the invention.

In the “base or salt” column, “base” represents a compound in free baseform, whereas “HCl” represents a compound in hydrochloride form. In thetable, OMe represents a methoxy group.

In the “m.p. (° C.) or M+H” column, m.p. (° C.) is the melting point ofthe compound in degrees Celsius and M+H is the value of the mass of thecompound protonated with a hydrogen atom (mass of the compound+1),determined by LC-MS (Liquid Chromatography-Mass Spectroscopy).

TABLE 1 (I)

m.p. (°C.) No R₁ m R₂ Base or salt or M + H  1

1 CH₂CONHCH₃ base 111-112  2.

1 CH₂CONHCH₃ base 121-122  3.

1 CH₂CONHCH₃ base 115-116  4.

1 CH₂CONHCH₃ base 154-155  5.

1 CH₂CONHCH₃ base 132-133  6.

1 CH₂CONHCH₃ base 132-133  7.

1 CH₂CONHCH₃ base 127-128  8.

1 CH₂CONHCH₃ base 151-152  9.

1 CH₂CONHCH₃ base 102-103  10.

1 CH₂CONHCH₃ base 102-103  11.

1 CH₂CONHCH₃ base 119-120  12.

1 CH₂CONHCH₃ base 119-120  13.

1 CH₂CONHCH₃ base 86-87  14.

1 CH₂CONHCH₃ base 121-122  15.

1 CH₂CONHCH₃ base 189-190  16.

1 CH₂CONHCH₃ base 113-114  17.

1 CH₂CONHCH₃ base 91-93  18.  19.

1 1 CH₂CONHCH₃ CH₂CONH₂ base base 124-125 M + H = 332  20.

1 CH₂CONHCH₃ base 171-172  21.

1 CH₂CONHCH₃ base 110-111  22.

1 CH₂CONHCH₃ base 125-126  23.

1 CH₂CONHCH₃ base 121-122  24.

1 CH₂CONHCH₃ base 121-122  25.

1 CH₂CONHCH₃ base 108-109  26.

1 CH₂CONHCH₃ base 123-124  27.

1 CH₂CONHCH₃ base 148-149  28.

1 CH₂CONHCH₃ base 165-166  29.

1 CH₂CONHCH₃ base 117-118  30.

1 CH₂CONHCH₃ HCl 172-174  31.

1 CH₂CONHCH₃ HCl 103-104  32.

1 CH₂CONHCH₃ HCl 199-200  33.

1 CH₂CONHCH₃ base 193-194  34.

1 CH₂CONHCH₃ base 180-181  35.

1 CH₂CONHCH₃ base 175-176  36.

1 CH₂CONHCH₃ base 197-198  37.

1 CH₂CONHCH₃ base 129-130  38.

1 CH₂CONHCH₃ base 207-208  39.

1 CH₂CONHCH₃ base 123-124  40.

1 CH₂CONHCH₃ base 202-203  41.

1 CH₂CONHCH₃ base 157-158  42.

1 CH₂CONHCH₃ base 139-140  43.

1 CH₂CONHCH₃ base 215-216  44.  45.

1 1 CH₂CONHCH₃ CH₂CONH₂ base base 187-189 193-195  46.

1 CH₂CONHCH₃ HCl 199-200  47.

1 CH₂CONHCH₃ base 181-182  48.

1 CH₂CONHCH₃ base 164-165  49.

1 CH₂CONHCH₃ base 183-184  50.

1 CH₂CONHCH₃ base 180-181  51.

1 CH₂CONHCH₃ base M + H = 414  52.

1 CH₂CONHCH₃ base 132-133  53.

1 CH₂CONHCH₃ base 196  54.

1 CH₂CONHCH₃ base 227-228  55.

1 CH₂CONHCH₃ base 188-189  56.

1 CH₂CONHCH₃ base 187-189  57.

1 CH₂CONHCH₃ base 194-195  58.

1 CH₂CONHCH₃ base 117-118  59.

1 CH₂CONHCH₃ base 164-165  60.  61.  62.

1 CH₂CONHCH₃ CH₂CONHCH₂CH₃ CH₂CONHCH₂- cyclopropyl base base base138-140 159-161 141-143  63.

1 CH₂CONHCH₃ base 127-129  64.

1 CH₂CONHCH₃ base 163-165  65.

1 CH₂CONHCH₃ base 131-132  66.

1 CH₂CONHCH₃ base 87-89  67.  68.

1 CH₂CONHCH₃ CH₂CONHCH₂CH₃ base base 152-154 131-133  69.  70.

1 CH₂CONHCH₃ CH₂CONHCH₂- cyclopropyl base base 200-204 187-189  71.  72.

1 CH₂CONHCH₃ CH₂CONHCH₂CH₃ base base 170-172 146-148  73.

11 CH₂CONHCH₃ base 191-192  74.

1 CH₂CONHCH₃ base 128-129  75.

1 CH₂CONHCH₃ base 203-206  76.  77.

1 1 CH₂CONHCH₃ CH₂CONH₂ base base 158-160 186-188  78.  79.  80.  81. 82.

1 1 1 1 1 CH₂CONH₂ CH₂CONHCH₃ CH₂CONHCH₂CH₃ CH₂CONHCH₂- cyclopropylCH(CH₃)CONHCH₃ base base base base base 228-230 206-209 210-212 198-200198-200  83.

1 CH₂CONHCH₃ base 188-190  84.

1 CH₂CONHCH₃ base 185-187  85.  86.

1 1 CH₂CONHCH₃ CH₂CONH₂ base base 146-150 155-157  87.

1 CH₂CONHCH₃ base 151-53  88.

1 CH₂CONHCH₃ base 198-202  89.

1 CH₂CONHCH₃ base 154-158  90.  91.

1 1 CH₂CONH₂ CH₂CONHCH₃ base base 208-210 190-191  92.  93.

1 1 CH₂CONH₂ CH₂CONHCH₃ base base 188-190 166-168  94.

1 CH₂CONHCH₃ base 181-183  95.  96.

1 1 CH₂CONH₂ CH₂CONHCH₃ base base 218-220 188-190  97.

2 CH₂CONHCH₃ base 156-158  98.

2 CH₂CONHCH₃ base 204-206  99.

2 CH₂CONHCH₃ base 174-176 100.

2 CH₂CONHCH₃ base 109-111 101.

2 CH₂CONHCH₃ base 124-126 102.

2 CH₂CONHCH₃ base 155-157 103.

2 CH₂CONHCH₃ base 191-193 104.

2 CH₂CONHCH₃ base M + H = 437 105.

2 CH₂CONHCH₃ base 167-170 106.

2 CH₂CONHCH₃ base 124-126

The compounds of the invention were subjected to pharmacological teststo determine their inhibitory effect on the enzyme FAAH (Fatty AcidAmido Hydrolase).

The inhibitory activity was demonstrated in a radioenzymatic test basedon measurement of the product of hydrolysis (ethanolamine [1-³H]) ofanandamide [ethanolamine 1-³H] with FAAH (Life Sciences (1995), 56,1999-2005 and Journal of Pharmacology and Experimental Therapeutics(1997), 283, 729-734). Thus, mouse brains (minus the cerebellum) areremoved and stored at −80° C. The membrane homogenates are preparedextemporaneously by homogenizing the tissues with a Polytron machine in10 mM Tris-HCl buffer (pH 8) containing 150 mM NaCl and 1 mM EDTA. Theenzymatic reaction is then performed in 70 μl of buffer containingfatty-acid-free bovine serum albumin (1 mg/ml). The various testcompounds at different concentrations, anandamide [ethanolamine 1-³H](specific activity of 15-20 Ci/mmol) diluted to 10 μM with coldanandamide, and the membrane preparation (400 μg of thawed tissue pertest) are successively added. After 15 minutes at 25° C., the enzymaticreaction is quenched by adding 140 μL of chloroform/methanol (2:1). Themixture is stirred for 10 minutes and then centrifuged for 15 minutes at3500×g. An aliquot (30 μL) of the aqueous phase containing theethanolamine [1-³H] is counted by liquid scintillation.

Under these conditions, the most active compounds of the invention haveIC₅₀ values (concentration inhibiting 50% of the control enzymaticactivity of FAAH) of between 0.001 and 1 μM.

Table 2 below presents the IC₅₀ values of a number of compoundsaccording to the invention.

TABLE 2 Compound No IC₅₀ 34 0.020 μM 37 0.190 μM 43 0.044 μM 44 0.007 μM76 0.290 μM 83 0.012 μM

It is thus seen that the compounds according to the invention haveinhibitory activity on the enzyme FAAH. The in vivo activity of thecompounds of the invention was evaluated in a test of analgesia.

Thus, the intraperitoneal (i.p.) administration of PBQ(phenylbenzoquinone, 2 mg/kg in a 0.9% sodium chloride solutioncontaining 5% ethanol) to male OF1 mice weighing 25 to 30 g causesabdominal stretching, on average 30 twists or contractions in the periodfrom 5 to 15 minutes after injection. The test compounds areadministered orally as a 0.5% suspension in Tween 80, 60 minutes or 120minutes before the administration of PBQ. Under these conditions, themost powerful compounds of the invention reduce the number of stretchesinduced by PBQ by 35 to 70%, in a dosage range of between 1 and 30mg/kg.

Table 3 below shows the results of the analgesia test for a number ofcompounds according to the invention.

TABLE 3 Reduction of Compound the number No of stretches (%) 37 −57 (a)44 −53 (a) 76 −47 (a) (a) 1 mg/kg p.o. at 2 hours.

The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121)catalyses the hydrolysis of the endogenous derivatives of amides and ofesters of various fatty acids, such as N-arachidonoylethanolamine(anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or2-arachidonoylglycerol. These derivatives exert various pharmacologicalactivities by interacting, inter alia, with the cannabinoid andvanilloid receptors.

The compounds of the invention block this degradation pathway andincrease the tissue content of these endogenous substances. They may beused in this respect in the prevention and treatment of pathologies inwhich the endogenous cannabinoids, and/or any other substratemetabolized by the enzyme FAAH, are involved. Mention may be made, forexample, of the following diseases and complaints:

pain, especially acute or chronic pain of neurogenic type: migraine,neuropathic pain including the forms associated with herpes virus anddiabetes; acute or chronic pain associated with inflammatory diseases:arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout,vasculitis, Crohn's disease, irritable bowel syndrome; acute or chronicperipheral pain; vertigo; vomiting; nausea, in particular nauseafollowing chemotherapy; eating disorders, in particular anorexia andcachexia of diverse nature; neurological and psychiatric pathologies:trembling, dyskinesia, dystonia, spasticity, compulsive and obsessivebehavior, Tourette's syndrome, all forms of depression and anxiety ofany nature or origin, mood disorders, psychosis; acute and chronicneurodegenerative diseases: Parkinson's disease, Alzheimer's disease,senile dementia, Huntington's chorea, lesions associated with cerebralischaemia and with cranial and medullary trauma; epilepsy; sleepingdisorders, including sleeping apnea; cardiovascular diseases, inparticular hypertension, cardiac arrhythmia, arteriosclerosis, heartattack, cardiac ischaemia; renal ischaemia; cancers: benign skin tumors,papillomas and cerebral tumors, prostate tumors, cerebral tumors(glioblastomas, medullo-epitheliomas, medulloblastomas, neuroblastomas,tumors of embryonic origin, astrocytomas, astroblastomas, ependyomas,oligodendrogliomas, plexus tumor, neuroepitheliomas, tumor of the pinealgland, ependymoblastomas, malignant meningiomas, sarcomatoses, malignantmelanomas, schwennomas); disorders of the immune system, especiallyautoimmune diseases: psoriasis, lupus erythematosus, connective tissuediseases, Sjögrer's syndrome, ankylosing spondylarthritis,undifferentiated spondylarthritis, Behcet's disease, haemolyticautoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis,amylosis, graft rejection, diseases affecting the plasmocytic line;allergic diseases: immediate or delayed hypersensitivity, allergicrhinitis or conjunctivitis, contact dermatitis; parasitic, viral orbacterial infectious diseases: AIDS, meningitis; inflammatory diseases,especially articular diseases: arthritis, rheumatoid arthritis,osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease,irritable bowel syndrome; osteoporosis; ocular complaints: ocularhypertension, glaucoma; pulmonary diseases: diseases of the respiratorypathways, bronchospasms, coughing, asthma, chronic bronchitis, chronicobstruction of the respiratory pathways, emphysema; gastrointestinaldiseases: irritable bowel syndrome, intestinal inflammatory disorders,ulcers, diarrhea; urinary incontinence and inflammation of the bladder.

The use of the compounds according to the invention, in the form ofbase, of pharmaceutically acceptable acid-addition salt, of hydrate orof solvate, for the preparation of a medicament for treating thepathologies mentioned above forms an integral part of the invention.

A subject of the invention is also medicaments comprising a compound offormula (I), or a pharmaceutically acceptable acid-addition salt, oralternatively a hydrate or solvate of the compound of formula (I). Thesemedicaments find their use in therapy, especially in the treatment ofthe pathologies mentioned above.

According to another of its aspects, the present invention relates topharmaceutical compositions containing, as active principle, at leastone compound according to the invention. These pharmaceuticalcompositions contain an effective dose of a compound according to theinvention, or a pharmaceutically acceptable acid-addition salt, or ahydrate, or a solvate, of the said compound, and optionally one or morepharmaceutically acceptable excipients.

The said excipients are chosen, according to the pharmaceutical form andthe desired mode of administration, from the usual excipients that areknown to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intrathecal, intranasal, transdermal, pulmonary, ocular or rectaladministration, the active principle of formula (I) above, or thepossible acid-addition salt thereof, or possible solvate or hydrate, maybe administered in a unit administration form, as a mixture withstandard pharmaceutical excipients, to animals and to human beings forthe prophylaxis or treatment of the above disorders or diseases.

The appropriate unit administration forms comprise the oral forms suchas tablets, soft or hard gel capsules, powders, granules, chewing gumsand oral solutions or suspensions, sublingual, buccal, intratracheal,intraocular or intranasal administration forms, the forms foradministration by inhalation, the subcutaneous, intramuscular orintravenous administration forms and the rectal or vaginaladministration forms. For topical application, the compounds accordingto the invention may be used in creams, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in the form of a tablet may comprise the followingcomponents:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose 6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

The said unit forms are dosed to allow a daily administration of from0.01 to 20 mg of active principle per kg of body weight, according tothe galenical form.

There may be particular cases in which higher or lower doses areappropriate, and such doses are also included in the invention.According to the usual practice, the dosage that is appropriate for eachpatient is determined by the doctor according to the mode ofadministration, and the weight and response of the said patient.

According to another of its aspects, the invention also relates to amethod for treating the pathologies indicated above, which comprises theadministration of an effective dose of a compound according to theinvention, an addition salt thereof with a pharmaceutically acceptableacid, a solvate or a hydrate of the said compound.

1. A compound of the formula (I):

wherein m represents an integer equal to 2; R₁ represents a group chosenfrom phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,oxazolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,cinnolinyl, naphthyridinyl, benzofuryl, dihydrobenzofuryl, benzothienyl,dihydrobenzothienyl, indolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl,pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl,dihydrothienopyridyl, imidazopyridyl, imidazopyrimidinyl,pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl orisothiazolopyridyl; wherein said group is optionally substituted withone or more groups R₃, which may be identical or different, or with agroup R₄; R₂ represents a group of formula CHR₅CONHR₆; R₃ represents ahalogen atom or a hydroxyl, cyano, nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-thioalkyl, C₁₋₆-fluoroalkyl, C₁₋₆-fluoroalkoxy,—O—(C₂₋₃-alkylene)-, —O—(C₁₋₃-alkylene)-O—, C₁₋₆-fluorothioalkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkylene, piperidyl, benzyloxy,piperazinyl, pyrrolidinyl, morpholinyl, phenyloxy, NR₇R₈, NHCOR₇,NHSO₂R₇, COR₇, CO₂R₇, CONR₇R₈, SO₂R₇ or SO₂NR₇R₈ group; R₄ represents agroup chosen from phenyl, benzofuryl, naphthyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, oxazolyl, triazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, triazolyl, quinolyl, tetrahydroquinolyl,isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, cinnolinyl, benzothienyl, indolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzimidazolyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl,imidazopyrimidinyl, pyrazopyridyl, oxazolopyridyl, isoxazolopyridyl,thiazolopyridyl or isothiazolo-pyridyl; wherein said group R₄ isoptionally substituted with one or more groups R₃, which may beidentical or different; R₅ represents a hydrogen atom or a C₁₋₃-alkylgroup; R₆ represents a hydrogen atom or a C₁₋₆-alkyl, C₃₋₇-cycloalkyl orC₃₋₇-cycloalkyl-C₁₋₃-alkylene group; and R₇ and R₈ represent,independently of each other, a hydrogen atom, a C₁₋₃-alkyl group or aphenyl group; or a salt thereof.
 2. The compound of formula (I)according to claim 1, wherein: R₁ represents a group chosen from phenyl,pyridyl, pyrimidinyl, pyrazinyl, naphthyl, quinolyl, isoquinolyl,benzisoxazolyl or thienopyridyl; wherein said group is optionallysubstituted with one or more groups R₃, which may be identical ordifferent; R₂ represents a group of formula CHR₅CONHR₆; R₃ represents ahalogen atom or a cyano, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl,C₁₋₆-fluoroalkoxy, —O—(C₂₋₃-alkylene)- or phenyloxy group; R₅ representsa hydrogen atom; and R₆ represents a hydrogen atom or a C₁₋₆-alkylgroup.
 3. The compound of formula (I) according to claim 1, wherein: R₁represents a group chosen from pyridyl, pyrimidinyl, pyrazinyl, quinolylor isoquinolyl; wherein said group is optionally substituted with agroup R₃; R₂ represents a group of formula CHR₅CONHR₆; R₃ represents ahalogen atom, or a C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-fluoroalkyl group; R₅represents a hydrogen atom; and R₆ represents a hydrogen atom or aC₁₋₆-alkyl group.
 4. The compound of formula (I) according to claim 1,wherein: R₁ represents a group chosen from phenyl, pyridyl, pyridazinyl,pyrimidinyl or thiadiazolyl; wherein said group is optionallysubstituted with a group R₄; R₄ represents a group chosen from phenyl,benzofuryl or naphthyl; wherein said group R₄ is optionally substitutedwith one or more groups R₃, which may be identical or different; R₂represents a group of formula CHR₅CONHR₆; R₃ represents a halogen atomor a nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl,C₁₋₆-fluoroalkoxy, —O—(C₁₋₃-alkylene)-O— or benzyloxy group; R₅represents a hydrogen atom; and R₆ represents a hydrogen atom or aC₁₋₆-alkyl or C₃₋₇-cycloalkyl-C₁₋₃-alkylene group.
 5. The compound offormula (I) according to claim 1, wherein R₁ represents a group chosenfrom phenyl, pyridyl, pyridazinyl or pyrimidinyl; wherein said group isoptionally substituted with a group R₄; R₄ represents a group chosenfrom phenyl, benzofuryl and naphthyl; wherein said group R₄ isoptionally substituted with one or more groups R₃, which may beidentical or different; R₂ represents a group of formula CHR₅CONHR₆; R₃represents a halogen atom or a nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-fluoroalkyl, C₁₋₆-fluoroalkoxy, —O—(C₁₋₃-alkylene)-O— or benzyloxygroup; R₅ represents a hydrogen atom; and R₆ represents a hydrogen atomor a C₁₋₆-alkyl group.
 6. A process for preparing a compound of formula(I) according to claim 1, comprising the step of: reacting an amine ofgeneral formula (II):

in which R₁ and m are as defined in the formula (I) according to claim1, with a carbonate of formula (III):

in which Z represents a hydrogen atom or a nitro group and R₂ is asdefined in the formula (I) according to claim
 1. 7. A process forpreparing a compound of formula (I) according to claim 1, comprising thestep of: converting the carbamate-ester of formula (Ia):

in which m, R₁ and R₅ are as defined in the formula (I) according toclaim 1 and R represents a methyl or ethyl group, via aminolysis usingan amine of formula R₆NH₂ in which R₆ is as defined in the formula (I)according to claim
 1. 8. A compound, which is 2-(methylamino)-2-oxoethyl4-nitrophenyl carbonate of formula:


9. A compound of the formula (Ia):

wherein m represents an integer equal to 2; R represents a methyl orethyl group; R₁ represents a group chosen from phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, triazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl,tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl,quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzofuryl,dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzimidazolyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl,imidazopyrimidinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl,thiazolopyridyl or isothiazolopyridyl; wherein said group is optionallysubstituted with one or more groups R₃, which may be identical ordifferent, or with a group R₄; R₃ represents a halogen atom or ahydroxyl, cyano, nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-thioalkyl,C₁₋₆-fluoroalkyl, C₁₋₆-fluoroalkoxy, —O—(C₂₋₃-alkylene)-,—O—(C₁₋₃-alkylene)-O—, C₁₋₆-fluorothioalkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkylene, piperidyl, benzyloxy, piperazinyl,pyrrolidinyl, morpholinyl, phenyloxy, NR₇R₈, NHCOR₇, NHSO₂R₇, COR₇,CO₂R₇, CONR₇R₈, SO₂R₇ or SO₂NR₇R₈ group; R₄ represents a group chosenfrom phenyl, benzofuryl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, oxazolyl, triazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, cinnolinyl, benzothienyl, indolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl,indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl,thienopyridyl, dihydrothienopyridyl, imidazopyridyl, imidazopyrimidinyl,pyrazopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl orisothiazolo-pyridyl; wherein said group R₄ is optionally substitutedwith one or more groups R₃, which may be identical or different; R₅represents a hydrogen atom or a C₁₋₃-alkyl group; and R₇ and R₈represent, independently of each other, a hydrogen atom, a C₁₋₃-alkylgroup or a phenyl group.
 10. A pharmaceutical composition comprising atleast one compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof in combination with one or morepharmaceutically acceptable excipients.
 11. A method of treating adisease selected from the group consisting of acute or chronic pain,vertigo, vomiting, nausea, eating disorder, sleeping disorder and renalischaemia, comprising administering to a patient in need of saidtreatment a therapeutically effective amount of a compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof.12. A method of treating a disease selected from the group consisting ofacute or chronic pain, vertigo and sleeping disorder, comprisingadministering to a patient in need of said treatment a therapeuticallyeffective amount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof.
 13. A method of treating adisease selected from the group consisting of hypertension, cardiacarrhythmia, arteriosclerosis, heart attack, cardiac ischaemia and renalischaemia comprising administering to a patient in need of saidtreatment a therapeutically effective amount of a compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof.14. A method of treating a disease selected from the group consisting oftrembling, dyskinesia, dystonia, spasticity, compulsive and obsessivebehavior and Tourette's syndrome comprising administering to a patientin need of said treatment a therapeutically effective amount of acompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 15. A method of treating a disease selectedfrom the group consisting of depression, anxiety, mood disorder andpsychosis comprising administering to a patient in need of saidtreatment a therapeutically effective amount of a compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof.16. A method of treating a disease selected from the group consisting ofParkinson's disease, Alzheimer's disease, senile dementia, Huntington'schorea and lesions associated with cerebral ischaemia and with cranialand medullary trauma comprising administering to a patient in need ofsaid treatment a therapeutically effective amount compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof.17. A method of treating a disease selected from the group consisting ofbenign skin tumor, papillomas and cerebral tumor, prostate tumor,glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas,tumors of embryonic origin, astrocytomas, astroblastomas, ependyomas,oligodendrogliomas, plexus tumor, neuroepitheliomas, tumor of the pinealgland, ependymoblastomas, malignant meningiomas, sarcomatoses, malignantmelanomas and schwannomas comprising administering to a patient in needof said treatment a therapeutically effective amount of a compound offormula (I) according to claim 1, or a pharmaceutically acceptable saltthereof.
 18. A method of treating a disease selected from the groupconsisting of psoriasis, lupus erythematosus, connective tissuediseases, Sjögrer's syndrome, ankylosing spondylarthritis,undifferentiated spondylarthritis, Behcet's disease, haemolyticautoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis,amylosis, graft rejection and diseases affecting the plasmocytic linecomprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim 1, or a pharmaceutically acceptable salt thereof.
 19. A methodof treating a disease selected from the group consisting of immediate ordelayed hypersensitivity, allergic rhinitis or conjunctivitis andcontact dermatitis comprising administering to a patient in need of saidtreatment a therapeutically effective amount of a compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof.